Inhibition of integrin α Vβ6 changes fibril thickness of stromal collagen in experimental carcinomas.
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Olof Olsson P, Gustafsson R, Salnikov AV, Göthe M, Zeller KS, Friman T, Baldetorp B, Koopman LA, Weinreb PH, Violette SM, Kalamajski S, Heldin NE, Rubin K
Cell Commun. Signal 16 (1) 36 [2018-07-02; online 2018-07-02]
Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF-β1 and -β3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma. The potential role of α Vβ6 integrin-mediated activation of latent TGF-β was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal αVβ6 integrin-specific monoclonal antibody 3G9 was used to inhibit the αVβ6 integrin activity. Both KAT-4 and Capan-2 cells expressed the α Vβ6 integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-β in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-β1 and -β3 reduced collagen fibril thickness in both tumor models. Our data demonstrate that the α Vβ6-directed activation of latent TGF-β plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to αVβ6 inhibition depends on the simultaneous presence of alternative paths for latent TGF-β activation and the extent of desmoplasia.
PubMed 29966518
DOI 10.1186/s12964-018-0249-7
Crossref 10.1186/s12964-018-0249-7
pii: 10.1186/s12964-018-0249-7
pmc: PMC6027735